Respiratory syncytial virus (RSV) is an enveloped, negative-sense RNA virus that is one of many serious pathogens in the Paramyxoviridae family. RSV is a leading cause of serious lower respiratory tract infections in infants. 2-3% of children with RSV require hospitalization, making it the most frequent cause of hospitalization in children under age 2 in the US and age 5 worldwide (Hall et al., 2009, N. Eng. J. Med. 360:588-98; Nair et al., 2010, Lancet 375:1545-1555). Nearly everyone contracts RSV by 2 years of age, and reinfection occurs throughout life because immunity after infection is neither complete nor durable (Domachowske & Rosenberg, 1999, Clin. Microbiol. Rev. 12:298-309; Glezen et al., 1981, J. Pediatr. 98:708-15). Severe RSV early in life may have long-term sequelae, as it is a risk factor for asthma in adolescence (Gem, 2008, Pediatr. Infect. Dis. 27:S97-103). Recent studies show that RSV commonly causes severe cold-like symptoms in healthy adults (Hashem, 2003, J. Clin. Virol. 27:14-21). Furthermore, RSV is a significant cause of morbidity and mortality in the elderly, with mortality rates as high as 8% in elderly with congestive heart failure or chronic pulmonary disease (Falsey et al., 2005, N. Engl. J. Med. 352:1749-59). The overall RSV burden on the US healthcare system is estimated to be ˜$2 billion annually (Falsey et al., 2005, N. Engl. J. Med. 352:1749-59; Makari et al., 2009, Manag. Care 18:2-7).
Currently, no vaccines or safe and effective RSV therapeutics are available, and treatment is limited to supportive care and, for the most desperate cases, administration of ribavirin, a broad antiviral with questionable efficacy and known toxicity (Broughton & Greenough, 2004, Curr. Opin. Investig. Drugs 5:862-5). Synagis (palivizumab), a monoclonal antibody (mAb) given prophylactically throughout RSV season, is partially effective at preventing the severe complications associated with RSV infection in the lower respiratory tract (Andabaka et al., 2013, Cochrane Database Syst. Rev. 4:CD006602). However, Synagis is only available to the highest risk infants and certain children <2 years old with chronic lung or congenital heart disease. Synagis is dosed at 15 mg/kg of body weight and a typical 5-month course for premature infants costs ˜$6,000. The high cost of Synagis prohibits its use in broader patient populations. Furthermore, it only reduces hospitalizations by 55% among high-risk infants (Palivizumab. Pediatrics, 1998, 102:531-7). Despite addressing only a small subset of potential RSV patients and its moderate efficacy, sales of Synagis in 2012 were >$1 billion. The FDA recently rejected a more potent follow-up antibody (motavizumab) due to increased toxicity and only “non-inferior” efficacy (trials were not designed to demonstrate superiority) (Carbonell-Estrany et al., 2010, Pediatrics 125:e35-51).
Several vaccine candidates are in early clinical development, but they must overcome the problems of early vaccine efforts that substantially exacerbated RSV infection by a still unclear mechanism (Rudraraju et al., 2013, Viruses 5:577-594). Additionally, since primary infection and maternal antibodies are often insufficient to provide adequate and lasting protection, it is clear that an effective vaccine would have to produce a superior immune response than natural infection. This goal is especially challenging in young infants with underdeveloped immune responses. Indeed, no vaccines for respiratory viruses are approved for use in infants <6 months old (Beeler & Eichelberger 2013, Microb. Pathog. 55:9-15).
There is a need for improved approaches to RSV treatment, for example, inhibitors of RSV entry into cells. The present disclosure provides approaches and embodiments addressing such needs and further provides other related advantages.